体内
药代动力学
化学
结合
抗体-药物偶联物
半胱氨酸
抗体
药理学
小分子
体外
碎片结晶区
组合化学
生物化学
受体
单克隆抗体
生物
免疫学
酶
生物技术
数学分析
数学
作者
Pamela Thompson,Ryan Fleming,Binyam Bezabeh,Feng‐Ying Huang,Shenlan Mao,Cui Chen,Jay Harper,Haihong Zhong,Xizhe Gao,Xiang-Qing Yu,Mary Jane Hinrichs,Molly Reed,Adeela Kamal,Patrick Strout,Song Cho,R. Jeremy Woods,Robert E. Hollingsworth,Rakesh Dixit,Herren Wu,Changshou Gao,Nazzareno Dimasi
标识
DOI:10.1016/j.jconrel.2016.06.025
摘要
Antibody-drug conjugates (ADCs) are among the most promising empowered biologics for cancer treatment. ADCs are commonly prepared by chemical conjugation of small molecule cytotoxic anti-cancer drugs to antibodies through either lysine side chains or cysteine thiols generated by the reduction of interchain disulfide bonds. Both methods yield heterogeneous conjugates with complex biophysical properties and suboptimal serum stability, efficacy, and pharmacokinetics. To limit the complexity of cysteine-based ADCs, we have engineered and characterized in vitro and in vivo antibody cysteine variants that allow precise control of both site of conjugation and drug load per antibody molecule. We demonstrate that the chemically-defined cysteine-engineered antibody-tubulysin conjugates have improved ex vivo and in vivo stability, efficacy, and pharmacokinetics when compared to conventional cysteine-based ADCs with similar drug-to-antibody ratios. In addition, to limit the non-target FcγRs mediated uptake of the ADCs by cells of the innate immune system, which may result in off-target toxicities, the ADCs have been engineered to lack Fc-receptor binding. The strategies described herein are broadly applicable to any full-length IgG or Fc-based ADC and have been incorporated into an ADC that is in phase I clinical development.
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